Huntington disease (HD) is a devastating inherited neurodegenerative disease without curative treatment. HD is the founding member of a large group of diseases due to polyglutamine accumulation and toxicity. There is a critical need for new insights in the pathophysiology of this disease, as well as for the identification of relevant molecules for clinical trials.
Several observations have led to the hypothesis that mitochondrial dysfunction has a role in polyglutamine diseases, and in Huntington disease in particular. Several lines of evidence indicate abnormal energy metabolism, including reduced glucose metabolism, elevated lactate levels and impaired mitochondrial-complex activity (Di Prospers and Fischbeck 2005, Nat Rev Genet 6(10): 756-65). To explain this abnormal energy metabolism most studies favoured a secondary impairment of the mitochondrial respiratory chain. An important decrease in complexes II & III (55%) has been shown in the caudate of HD patients (Gu 1996, Ann Neurol 39: 385-9), as well as a deficiency in complex 1 in muscle (Arenas 1998, Ann Neurol 43:397-400), therefore supporting the possibility of mitochondrial respiratory chain defects in pathogenesis of HD (Shapira 1998, Biochem Biophys Acta 1366: 225-33, Grunewald 1999, Ann N Y Acad Sci 893: 203-13). These findings correlated with HD models induced by 3-nitropropionic acid, an irreversible complex II inhibitor (Beal 1993, J Neurosci 13: 4181-92). However, these data are controverted by the demonstration of normal mitochondrial electron transport complexes in transgenic mice at an early stage (Guidetty 2001, Exp Neurol 169: 340-50), as well as in striatal cells in culture expressing mutant huntingtin, despite the significant reduction in ATP synthesis observed in those cells (Milakovic 2005, JBC 280: 30773-82). Additional indirect evidence for an energy defect in polyglutamine disease arise from the partial efficacy of energetic therapies, such as dichloroacetate (Andreassen 2001, Ann Neurol 50: 112-9), pyruvate (Ryu 2004, Exp Neurol 187: 150-9), creatine (Ferrante 2000, J Neurosci 20: 4389-97) and coenzyme Q10 (Schilling 2001, Neurosci Lett 315: 149-53) in mice models.
However, to date, effective pharmacotherapy for neurodegenerative disease associated with impaired energy metabolism like polyglutamine diseases in particular, remains rather elusive.